Treatment of HIV-Associated Cognitive Impairment

HIV 相关认知障碍的治疗

• 批准号: 8233952
• 负责人: Ana-Claire Lew Meyer
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233952
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adherence; Adult; Adverse effects; Affect; Africa South of the Sahara; Aftercare; Ambulatory Care; Anti-Retroviral Agents; Area; Award; Basic Science; Biomedical Research; Brain; California; Caring; Cerebrospinal Fluid; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Cognition; Cohort Studies; Collaborations; Communicable Diseases; Control Groups; Data; Developing Countries; Diagnosis; Diagnostic; Disease; Drug Kinetics; Education; Effectiveness; Enrollment; Environment; Epidemiology; Familiarity; Family; Funding; Future; Goals; HIV; HIV-1; Health; Health Sciences; Home environment; Immunology; Impaired cognition; Impairment; Incidence; Individual; Infection; Inflammation; Institution; International; Kenya; Laboratory Research; Lead; Measures; Mentored Research Scientist Development Award; Mentors; Methods; Neopterin; Nervous system structure; Neuraxis; Neurocognitive; Neurologic; Neurological outcome; Neurologist; Neurology; Neuropsychological Tests; Neuropsychology; Neurovirology; Observational Study; Patient Care; Patients; Penetration; Performance; Pharmaceutical Preparations; Physicians; Plasma; Prevalence; Price; Province; Proxy; RNA; Randomized Controlled Trials; Regimen; Reporting; Research; Research Infrastructure; Research Personnel; Research Training; Resources; Risk; Sampling; San Francisco; Services; Site; Testing; Training; Translational Research; Treatment Effectiveness; Tropical Medicine; Universities; Viral; Work; antiretroviral therapy; base; career; clinical research site; cohort; cost effective; design; effective intervention; effective therapy; experience; follow-up; functional status; global health; implementation science; improved; innovation; mortality; multidisciplinary; neurophysiology; neuropsychological; patient oriented; programs; prospective; psychologic; repository; research study; treatment program; virology

DESCRIPTION (provided by applicant): This is an application for a K01 award for Dr. Ana-Claire Meyer, a neurologist at the University of California, San Francisco. Dr. Meyer is establishing herself as a young investigator focused on patient-oriented clinical research on infectious diseases of the nervous system in resource-limited settings. Dr. Meyer will obtain additional research training through coursework, tutorials and practical experience in the following areas: applying state-of-the-art research and laboratory methods in tropical medicine, neurophysiology, neuropsychology and neurovirology to global health settings; designing and implementing clinical trials; and additional training in implementation science and global health. With this award, she will obtain the didactic training and mentored clinical research experience she needs to establish herself as an independent researcher and successfully compete for R01 funding. This K01 award will enable Dr. Meyer to take the next steps to achieve her long-term career goal: to become a leading researcher developing, evaluating, and implementing innovative and cost-effective interventions to diagnose and treat neurologic conditions in resource limited settings such as sub-Saharan Africa. The Environment: To support her career objectives and research plan, Dr. Meyer has assembled a multidisciplinary mentoring committee comprised of senior clinical investigators who will provide added expertise in conducting clinical, epidemiological, and translational research on HIV-associated neurocognitive disorders within an international collaborative. Her primary mentor is Dr. Richard W. Price, and her co-mentors are Drs. Gretchen Birbeck and Craig Cohen. Her developing country mentor will be Dr. Elizabeth Bukusi. Her home institution, the University of California San Francisco (UCSF), is considered one of the nation's premier health sciences, training, and research centers and has a well-established reputation in biomedical research. The Department of Neurology is a leading academic center dedicated to excellence in patient care, education and research. The HIV Neurology Research Program conducts clinical and basic science research on the effects of HIV on the nervous system and includes active collaborations with clinical HIV, virology and immunology programs. Her international collaborative site, Family AIDS Care and Education Services (FACES), is an HIV/AIDS care and treatment program based in Kenya. FACES currently provides HIV care in 83 facilities in Nyanza Province and Nairobi. As of December 31, 2010, FACES had 96,821 patients cumulatively enrolled with 37,310 patients on ART. FACES clinical sites have previous experience with research studies. In addition, FACES sites are staffed by well-trained clinicians and ancillary staff and have the necessary infrastructure and oversight to complete this study. Research Plan: We estimate that HIV-associated neurocognitive disorders (HAND) may affect nearly 188,000 individuals in Nyanza Province, Kenya, 5.5 million across sub-Saharan Africa, and 8.25 million worldwide. HAND has been associated with poor adherence to antiretroviral therapy (ART) and with higher mortality. Combination ART is the most effective treatment for HAND to date and some studies have suggested that ART with higher penetration into the central nervous system (CNS) lead to improved neurologic outcomes. However, these studies have important limitations and thus there is insufficient evidence to recommend ART with high CNS penetration effectiveness (CPE) for the treatment of HAND. The objective of this application is to determine whether it is important to treat HIV-infected individuals with neurocognitive disorders with ART with high CPE. Because of limited ART choices in Kenya, we will be able to directly compare the effects of specific ART regimens thus avoiding the limitations of prior studies. The central hypothesis is that, among individuals with HAND, ART with high CPE lead to improved neurologic outcomes as compared to ART with low CPE. We will enroll a prospective observational cohort of 200 HIV-infected ART- naove adults with HIV-associated cognitive impairment. Aim 1: To determine the effect of common ART regimens with different CNS pharmacokinetics on the neuro-psychological performance of ART-naove HIV infected adults with cognitive impairment in western Kenya Over a follow-up period of 48 weeks, we will determine the effect of four ART regimens on three NP measures: a composite score, the QNPZ-4, and level of impairment using common diagnostic criteria. Aim 2: To determine the effect of common ART regimens with different CNS pharmacokinetics on viral replication and inflammation in the cerebrospinal fluid (CSF) of ART-naove HIV infected adults with cognitive impairment in western Kenya In a sub-sample of 100 individuals, we will determine the effect of ART regimens on: (1) CSF HIV-1 RNA; (2) CSF:plasma HIV-1 RNA ratio; (3) CSF WBC count; (4) CSF neopterin. We will also create a unique repository of samples for future collaborative studies. Aim 3: To determine whether there is a practice effect on the neuropsychological test battery We will re-administer our NP battery to 100 HIV un-infected individuals who we have previously studied. These specific aims logically build toward an R01 to determine the effect of ART on combined systemic and neurologic outcomes in cognitively impaired individuals in a randomized controlled trial. PUBLIC HEALTH RELEVANCE: A better understanding of which antiretroviral therapies lead to the greatest improvements in cognition among individuals with HIV-associated neurocognitive disorders could help physicians better tailor antiretroviral therapy. Ultimately, this could lead to improved cognition, functional status and health for individuals with HIV-associated neurocognitive disorders.

描述（由申请人提供）：这是加州大学旧金山分校神经科医生 Ana-Claire Meyer 博士的 K01 奖项申请。迈耶博士正在将自己定位为一名年轻的研究者，专注于在资源有限的环境中以患者为中心的神经系统传染病临床研究。迈耶博士将通过以下领域的课程、辅导和实践经验获得额外的研究培训：将热带医学、神经生理学、神经心理学和神经病毒学领域最先进的研究和实验室方法应用于全球卫生环境；设计和实施临床试验；以及实施科学和全球健康方面的额外培训。凭借该奖项，她将获得所需的教学培训和指导临床研究经验，以确立自己作为独立研究员的地位，并成功竞争 R01 资金。该 K01 奖项将使 Meyer 博士能够采取下一步措施来实现她的长期职业目标：成为一名领先的研究人员，开发、评估和实施创新且具有成本效益的干预措施，以诊断和治疗撒哈拉以南非洲等资源有限地区的神经系统疾病。 环境：为了支持她的职业目标和研究计划，Meyer 博士组建了一个由高级临床研究人员组成的多学科指导委员会，他们将在国际合作中提供有关 HIV 相关神经认知障碍的临床、流行病学和转化研究方面的额外专业知识。她的主要导师是 Richard W. Price 博士，她的共同导师是 Drs. Richard W. Price。格雷琴·伯贝克和克雷格·科恩。她的发展中国家导师将是伊丽莎白·布库西博士。 她的母校加州大学旧金山分校 (UCSF) 被认为是美国首屈一指的健康科学、培训和研究中心之一，在生物医学研究方面享有盛誉。神经病学系是一个领先的学术中心，致力于卓越的患者护理、教育和研究。 HIV 神经学研究项目针对 HIV 对神经系统的影响进行临床和基础科学研究，并包括与临床 HIV、病毒学和免疫学项目的积极合作。她的国际合作网站家庭艾滋病护理和教育服务 (FACES) 是一个位于肯尼亚的艾滋病毒/艾滋病护理和治疗项目。 FACES 目前在尼安萨省和内罗毕的 83 个设施中提供艾滋病毒护理。截至2010年12月31日，FACES累计登记了96,821名患者，其中37,310名患者接受了ART。 FACES 临床中心以前有研究经验。此外，FACES 中心配备了训练有素的临床医生和辅助人员，并拥有完成这项研究所需的基础设施和监督。 研究计划：我们估计，艾滋病毒相关神经认知障碍 (HAND) 可能影响肯尼亚尼安萨省的近 188,000 人、撒哈拉以南非洲地区的 550 万人以及全世界的 825 万人。 HAND 与抗逆转录病毒治疗 (ART) 依从性差和死亡率较高有关。联合 ART 是迄今为止最有效的 HAND 治疗方法，一些研究表明，对中枢神经系统 (CNS) 具有更高渗透力的 ART 可以改善神经系统结果。然而，这些研究具有重要的局限性，因此没有足够的证据推荐具有高中枢神经系统渗透有效性（CPE）的ART来治疗HAND。本申请的目的是确定采用具有高 CPE 的 ART 治疗患有神经认知障碍的 HIV 感染者是否重要。由于肯尼亚的 ART 选择有限，我们将能够直接比较特定 ART 方案的效果，从而避免先前研究的局限性。核心假设是，在 HAND 患者中，与低 CPE 的 ART 相比，高 CPE 的 ART 可以改善神经系统结果。我们将招募 200 名患有 HIV 感染且患有 HIV 相关认知障碍的未接受 ART 治疗的成年人组成的前瞻性观察队列。 目标 1：确定具有不同 CNS 药代动力学的常见 ART 方案对肯尼亚西部患有认知障碍的未接受 ART 的 HIV 感染成人的神经心理表现的影响 在 48 周的随访期内，我们将确定四种 ART 方案对三种 NP 指标的影响：综合评分、QNPZ-4 和使用通用诊断标准的损伤水平。 目标 2：确定具有不同 CNS 药代动力学的常见 ART 方案对肯尼亚西部患有认知障碍的未接受 ART 的 HIV 感染成人脑脊液 (CSF) 中病毒复制和炎症的影响。在 100 名个体的子样本中，我们将确定 ART 方案对以下方面的影响：(1) CSF HIV-1 RNA； (2)脑脊液：血浆HIV-1 RNA比值； (3)脑脊液白细胞计数； (4)脑脊液新蝶呤。我们还将为未来的合作研究创建一个独特的样本存储库。 目标 3：确定神经心理学测试电池组是否有练习效果 我们将重新对我们之前研究过的 100 名未感染 HIV 的个体进行 NP 电池组测试。这些具体目标在逻辑上建立在 R01 的基础上，以确定 ART 对随机对照试验中认知受损个体的系统和神经系统综合结果的影响。 公共卫生相关性：更好地了解哪些抗逆转录病毒疗法可以最大程度地改善艾滋病毒相关神经认知障碍患者的认知能力，可以帮助医生更好地制定抗逆转录病毒疗法。最终，这可能会改善患有艾滋病毒相关神经认知障碍的个体的认知、功能状态和健康状况。